Recent molecular studies have disclosed that abrogated cell cycle control underlies a wide range of human tumors (Sherr, C. J., Science 274, 1672-7 (1996)). Genetic alteration in p53, RB1, or p16 genes is involved in a great majority of human cancers, where deregulated cell cycle progression results in uncontrolled cell proliferation (Hanahan, D. & Weinberg, R. A. Cell 100, 57-70 (2000); Sherr, C. J. & McCormick, F. Cancer Cell 2, 103-12 (2002)). Among the cell cycling, the G1/S boundary, wherein cell cycle is arrested, integrity of the genome is surveyed, and DNA damages are repaired, is critical for the maintenance of normal cellular and genomic properties. Two key signaling pathways, namely p53 and RB1, participate in the regulation of the G1/S boundary by controlling a number of downstream genes. Cells containing damaged DNA are arrested at this boundary by the induction p21Cip1 through transactivation of accumulated wild type p53 protein (Sherr, C. J. & Roberts, J. M. Genes Dev 13, 1501-12 (1999)). Isolated as a responsible gene for familial retinoblastoma (Friend, S. H. et al. Nature 323, 643-6 (1986).; Fung, Y. K. et al. Science 236, 1657-61 (1987); Lee, W. H. et al. Science 235, 1394-9 (1987)), RB1 functions as a tumor suppressor through the control of cell cycle progression. From the G1 to the S cell cycle transition, RB1 is inactivated by phosphorylation, which is catalyzed by cyclin dependent kinases (CDKs). Under phosphorylated RB1 inhibits the activator E2Fs, transcription factors that modulate expression of genes required for DNA replication and cell cycle progression (Dannenberg, J. H., et al., Genes Dev 14, 3051-64 (2000).; Sage, J. et al. Genes Dev 14, 3037-50 (2000)), by a direct interaction with their activation domain, alteration of chromatin structure complexed with HDACs, and recruitment of a repressor complex to E2F-binding site(s) in the promoter region of responsive genes (Weintraub, S. J., et al., Nature 358, 259-61 (1992).; Sellers, W. R., et al., Proc Natl Acad Sci USA 92, 11544-8 (1995)). Phosphorylated by CDK/cyclin complexes, such as CDK4/cyclinD, RB1 dissociates E2Fs, which then transactivate downstream genes including cyclin E, c-Myb, CDK2, and BCL2.
The present inventors previously reported that SMYD3 has a di- and tri-methyltransferase activity on lysine 4 of histone H3 (H3-K4), and that elevated SMYD3 expression plays a crucial role in the proliferation of colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC) cells (Hamamoto, R. et al., Nat Cell Biol 6, 731-40 (2004)), because over-expression of SMYD3 resulted in growth promotion of NIH3T3 cells and the knockdown of endogenous SMYD3 expression in several cancer cells induced a growth inhibition and apoptosis of those cells. However, the precise mechanism(s) by which SMYD3-overexpression results in growth promotion remains unresolved. Modification of histones by acetylation, phosphorylation, and/or methylation regulates chromatin structure that leads to transcriptional activation or inactivation of target gene(s) by recruiting different molecules. Regarding histone lysine methylation, modification of H3-K4, H3-K36, and H3-K79 is associated with a transcriptional activation by the conformational change from heterochromatin to euchromatin structure (Im, H. et al., J Biol Chem 278, 18346-52 (2003); Bannister, A. J. et al., J Biol Chem 280, 17732-6 (2005).; Schneider, R. et al., Nat Cell Biol 6, 73-7 (2004)), whereas methylation of H3-K9, H3-K27, and H4-K20 results in transcriptional repression by heterochromatin structure (Schotta, G. et al., Genes Dev 18, 1251-62 (2004).; Nakayama, J. et al., Science 292, 110-3 (2001).; Kirmizis, A. et al. Genes Dev 18, 1592-605 (2004)).